Background. Patients with HIV/AIDS-associated cryptococcal meningitis (CM) frequently experience clinical deterioration, known as cryptococcosis-associated IRIS (C-IRIS), upon initiation of ART. The immunological mechanisms underlying C-IRIS are incompletely defined and no reliable predictive biomarkers exist. We investigated whether plasma or CSF levels of cytokines and chemokines predicted C-IRIS and are potential predictive biomarkers. Methods. Patients with CM who experienced C-IRIS (N = 27) upon ART initiation were compared to CD4+ T-cell count–matched patients without C-IRIS (N = 27). Plasma and CSF collected pre-ART were assayed for cytokines and chemokines using a 17-plex Luminex kit or ELISA. Cox proportional hazards regression and principal component analyses were also performed. Results. Plasma IL-2, IL-4, IL-5, IL-7, IL-17, IFN-γ, and TNF-α levels were higher in C-IRIS patients compared to controls (all p < 0.05), with IL-5 and IL-7 significant after Bonferroni-Holm correction. In multivariate Cox proportional hazards regression, high IL-5 (hazard ratio [HR], 5.76 [95% CI : 0.77–43.0]; p = 0.088) and IL-7 (HR, 9.30 [1.96–44.0]; p = 0.005) were predictive of C-IRIS. Plasma IL-5 (p = 0.0008) and IL-10 (p = 0.0089) were lower in those who achieved CSF cryptococcal culture negativity compared to those with positive cultures pre-ART. There were no significant differences in CSF cytokine or chemokine levels between cases and controls. Conclusions. High plasma IL-5 and IL-7 levels pre-ART were associated with increased risk of developing C-IRIS. High IL-5 levels may reflect a Th2 environment associated with impaired clearance of cryptococci while high IL-7 levels may reflect IL-7/IL-7R pathway dysfunction in T cells, both of which could be associated with C-IRIS immunopathogenesis.